Neurogenesis is a vital process in the brains of animals and humans, whereby new nerve cells are continuously generated throughout the life span of the organism. The newly born cells are able to differentiate into functional cells of the central nervous system and integrate into existing neural circuits in the brain. Neurogenesis is known to persist throughout adulthood in two regions of the mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus. In these regions, multipotent neural progenitor cells (NPCs) continue to divide and give rise to new functional neurons and glial cells (for review Gage 2000). It has been shown that a variety of factors can stimulate adult hippocampal neurogenesis, e.g., adrenalectomy, voluntary exercise, enriched environment, hippocampus dependent learning and anti-depressants (Yehuda 1989, van Praag 1999, Brown J 2003, Gould 1999, Malberg 2000, Santarelli 2003). Other factors, such as adrenal hormones, stress, age and drugs of abuse negatively influence neurogenesis (Cameron 1994, McEwen 1999, Kuhn 1996, Eisch 2004).
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are ubiquitous second messengers that mediate a wide range of processes in mammalian cells, including vision, olfaction, platelet aggregation, aldosterone synthesis, insulin secretion, T cell activation, and smooth muscle relaxation. Cyclic nucleotide phosphodiesterases (“PDEs”) regulate intracellular levels of cAMP and cGMP by catalyzing their hydrolysis to the corresponding nucleotide 5′-monophosphates. Over 20 PDE genes have been cloned, encoding 11 gene families (PDE1-PDE11), which are classified according to sequence homology, as well as the biochemical and pharmacological properties of the encoded PDEs (e.g., specificity for cAMP and/or cGMP, response to modulatory compounds).
PDE families that specifically/preferentially hydrolyze cAMP include PDE4, PDE7, and PDE8, whereas families that specifically/preferentially hydrolyze cGMP include PDE5, PDE6, and PDE9. The PDE1, PDE2, PDE3, PDE10, and PDE11 families show substantial activity agonist both cAMP and cGMP. Many PDE gene families comprise multiple genes, which give rise to distinct isozymes. For example, the PDE3, PDE6, PDE7, and PDE8 families each comprise at least two genes (3A, 3B; 6A, 6B; 7A, 7B; 8A, 8B), while the PDE1 family comprises at least three genes (1A, 1B, 1C), and the PDE4 family comprises at least four genes (4A, 4B, 4C, 4D). In addition, the majority of PDE gene transcripts are subject to alternative splicing, giving rise to multiple isozymes within each family. PDE isozymes are differentially expressed in various tissues, cell types, and subcellular locations, and numerous PDE isozymes have been detected throughout the CNS.
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